Dramatic progress has been made in recent years identifying mutational events in tumor cells that lead to progression to the malignant phenotype. However, it has become apparent that the full expression of this malignant phenotype is modulated by the tumor microenvironment. In breast cancers, the topic of this application, this consists of many cell types including fat cells, fibroblasts and immune cells. In the latter class, macrophages are notable in their abundance and in clinical studies an increase in their density is correlated with poor prognosis. Research by the PI has shown that these macrophages play important roles in tumor progression and metastasis. These and others studies have led us to propose six separate traits whereby macrophages can promote tumor progression and metastasis. These are chronic inflammation, matrix remodeling, tumor cell invasion, intravasation, angiogenesis and seeding at distant sites. This led to the hypothesis that the tumor microenvironment educates macrophages to perform specific tasks. Nevertheless, in other contexts macrophages can kill tumor cells and present antigens to cytotoxic T cells. This has led to the concept that tumors evolve to avoid immune destruction and to enhance the trophic roles of these immune cells. In this proposal in three projects, in human breast cancers and mouse models we will define the mechanistic interactions between tumor cells, the immune system and other components of the microenvironment that results in tumor progression and metastasis. Project 1: Natural History of immune responses in a mouse model of spontaneous breast cancer. This addresses the hypothesis that the tumor microenvironment biases the local immune response away from a cytotoxic one to a benign or trophic one through the recruitment of regulatory T cells and myeloid cells. Project 2; The role of macrophages in breast cancer angiogenesis. This will define the mechanism that macrophages employ to enhance angiogenesis in the tumor. Project 3: Novel Methods for Detecting Cell Interactions in the Tumor Microenvironment. This uses nanotechnology to miniaturize an artificial blood vessel that can in dwell in human tumor xenografts and ultimately in human tumors that can report on the status of cell collection and diagnose invasive tumors.